Abstract 246: Global Analysis of Differentially Expressed Genes in the Aortae of Apoe-deficient Mice Infused with Insulin-like Growth Factor I: Novel Mechanisms of the Anti-atherogenic Effect of IGF-1

We have previously shown that insulin like growth factor-I (IGF-1) suppresses atherosclerosis progression in ApoE-null mice. To determine mechanisms, ApoE-null mice were chronically infused with IGF-1 (1.5 mg/kg/d, 12 weeks) or saline (control) or treated short-term with IGF-1 (0.4 mg/kg/d, i.p., 1 week) or saline (control). Aortic gene expression of 84 atherosclerosis-related genes-of-interest was analyzed with RT-PCR arrays. Chronic IGF-1 infusion decreased expression levels of pro-apoptotic molecules (Bax, 0.62, BID, 0.26), adhesion molecules (integrin β2, 0.32, integrin α2, 0.28, VCAM-1, 0.43), pro-inflammatory cytokines (TNFα, 0.22, interferon γ, 0.30) and lipoprotein lipase (LPL, an enzyme mediating lipid hydrolysis and tissue uptake of oxidized low density lipoprotein (OxLDL), 0.69). These changes in gene expression correlated with a reduction in atherosclerotic plaque burden (Oil Red-positive aortic valve lesion area, ×000 pixels², IGF-1, 228±13, saline, 268±22), suppression of plaque apoptosis (% apoptotic cells per plaque, IGF-1, 3.4±0.7, saline, 5.8±0.5, P<0.05, TUNEL assay), decrease in plaque TNFα levels (58% reduction vs. saline, P<0.05, immunostaining), and inhibition of serum LPL activity (IGF-1, 1.1±0.2, saline, 3.7±0.4, P<0.05, fluorescence assay). Short-term IGF-1 treatment similarly decreased mRNA levels of Bax (0.68), BID (0.61), integrin β2 (0.62), TNFα (0.50), interferon γ (0.37), LPL (0.42) and also downregulated a group of scavenger receptors (CD36, 0.44, MSR-1, 0.48, MSR-2, 0.52). To further characterize the effect of IGF-1 on LPL we exposed THP-1-derived macrophages to OxLDL (80 ug/ml, 16 h) in the presence or absence of IGF-1. OxLDL increased LPL activity in conditioned media (>5 fold, P<0.01), but pre-treatment with IGF-1 (25 ng/ml, 24 h) reversed LPL upregulation by 52% and suppressed lipid internalization by 88% (P<0.05, Oil Red staining). In summary IGF-1 reduces pro-inflammatory cytokines, pro-apoptotic molecules, adhesion molecules, scavenger receptors, and lipoprotein lipase expression in ApoE-null mice and markedly blunts OxLDL-induced upregulation of LPL and lipid uptake in THP-derived macrophages. These data provide major insights into mechanisms whereby IGF-1 is atheroprotective.